Submissions for variant NM_004612.4(TGFBR1):c.451C>T (p.Arg151Cys)

gnomAD frequency: 0.00001  dbSNP: rs776680716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816693	SCV000957211	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 151 of the TGFBR1 protein (p.Arg151Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 27879313). ClinVar contains an entry for this variant (Variation ID: 659659). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001171875	SCV001334760	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000816693	SCV001359428	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-01	criteria provided, single submitter	clinical testing	This variant is located in the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with thoracic aortic disease (PMID: 27879313). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002478902	SCV002788687	uncertain significance	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2021-08-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001791	SCV004840379	uncertain significance	Loeys-Dietz syndrome	2024-01-08	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the TGFBR1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.